# Identification of Ferroptosis-Related Hub Genes Linked to Suppressed Sulfur Metabolism and Immune Remodeling in Schistosoma japonicum-Induced Liver Fibrosis

## TL;DR

This study identifies key genes linked to liver fibrosis caused by S. japonicum infection, revealing their roles in sulfur metabolism and immune changes.

## Contribution

The study introduces 7 novel ferroptosis-related hub genes associated with suppressed sulfur metabolism and immune remodeling in schistosomal liver fibrosis.

## Key findings

- Seven hub genes (Lcn2, Timp1, Cth, Cp, Hmox1, Cbs, Gclc) were identified as key regulators in S. japonicum-induced liver fibrosis.
- Downregulation of Cth, Cbs, and Gclc suggests impaired antioxidant defenses, while upregulation of Timp1, Lcn2, and Hmox1 indicates pro-fibrotic and pro-inflammatory activity.
- The hub genes are associated with immune infiltration by neutrophils and eosinophils, and Timp1 showed perfect diagnostic potential with an AUC of 1.000.

## Abstract

Liver fibrosis induced by Schistosoma japonicum Katsurada, 1904 (S. japonicum) infection lacks effective diagnostic markers and specific anti-fibrotic therapies. Although dysregulated iron homeostasis and ferroptosis pathways may contribute to its pathogenesis, the core regulatory mechanisms remain elusive. To unravel the ferroptosis-related molecular features, this study integrated transcriptomic datasets (GSE25713 and GSE59276) from S. japonicum-infected mouse livers. Following batch effect correction and normalization, ferroptosis-related differentially expressed genes (FRDEGs) were identified. Subsequently, core hub genes were screened through the construction of a protein–protein interaction (PPI) network, functional enrichment analysis, immune infiltration evaluation, and receiver operating characteristic (ROC) analysis. The expression patterns of these hub genes were further validated in an S. japonicum-infected mouse model using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The study identified 7 hub genes (Lcn2, Timp1, Cth, Cp, Hmox1, Cbs, and Gclc) as key regulatory molecules. Functional enrichment analysis revealed that these hub genes are closely associated with sulfur amino acid metabolism and oxidative stress responses. Specifically, key enzymes involved in cysteine and glutathione (GSH) synthesis (Cth, Cbs, Gclc) were consistently downregulated, suggesting a severe impairment of the host antioxidant defense capacity. Conversely, pro-fibrotic and pro-inflammatory markers (Timp1, Lcn2, Hmox1) were upregulated. This molecular pattern was significantly associated with a remodeled immune microenvironment, characterized by increased infiltration of neutrophils and eosinophils. In vivo validation confirmed the expression trends of 6 hub genes, corroborating the bioinformatics predictions, while the discrepancy in Cp expression highlighted the complexity of post-transcriptional regulation in vivo. The identified hub genes demonstrated excellent diagnostic potential, with Timp1 achieving an area under the curve (AUC) of 1.000. This study elucidates the molecular link between S. japonicum infection and the ferroptosis pathway, suggesting that these hub genes may drive liver fibrosis progression by regulating sulfur metabolism and the immune microenvironment. These findings offer potential diagnostic biomarkers and novel therapeutic targets for schistosomal liver fibrosis.